CD27L (CD70, TNFSF7) is a type II integral membrane protein whose expression on normal tissues is highly restricted to a subset of activated T and B cells, dendritic cells and to a small subset of cells in the thymic epithelium. The biological functions of CD27L, which include augmentation or regulation of the immune response, are mediated via binding to its receptor, CD27, which is expressed predominately on lymphoid cells. CD27L/CD27 interactions regulate B-cell proliferation and differentiation and T-cell costimulation/activation. Disruption of the CD27L/CD27 interaction in mice deficient for CD27 does not result in any phenotype in the absence of an immune challenge. (Grewal, Expert Opin. Ther. Targets. 12, 341-351 (2008)).
In addition to its very restricted expression on normal tissues, CD27L is expressed at relatively high levels in some B cell non-Hodgkin's lymphoma (B-NHL) tumor sub-types, in pre-B cell acute lymphocytic leukemia (ALL) and in B cell type-chronic lymphocytic leukemia (B-CLL). Aberrant expression of CD27L is also observed in renal cell carcinoma (RCC) but not in normal kidney or other normal tissues. Thus, CD27L comes close to exhibiting properties consistent with those of a “tumor specific antigen” (Grewal, Expert Opin. Ther. Targets. 12, 341-351 (2008)).
Each year, of the approximately 49,000 patients that will develop RCC, a little over 40,000 of those will be diagnosed with ccRCC in the US (American Cancer Society: Cancer Facts and Figures final (2008). While some newer therapeutics have been approved for RCC over the last 4 years, the 5 year survival rate for patients with metastatic RCC remains dismal at 10-20% (National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis—accessed 2008) and significant unmet medical need remains. The projected yearly number of newly diagnosed ccRCC patients (U.S.) that are expected to express CD27L is approximately 36,000. There are an estimated 64,000 ccRCC patients currently with active disease.
Of the B-cell malignancies reported to aberrantly express CD27L, the B-NHL subsets of diffuse large cell B-cell lymphoma (DLBCL) and follicular lymphoma (FL) show the highest incidence of expression ranging from 33% for FL to 71% for DLBCL as assessed by IHC on frozen sections using a validated antibody (Lens et al., Brit. J. Hematol. 106, 491-503 (1999). 50-89% of B-CLL tumors also express CD27L as assessed by IHC on frozen tumor sections or by flow cytometry on circulating tumor cells (Ranheim et al., Blood 85, 3556-3565 (1965); Trentin et al., Cancer Res. 57, 4940-4947 (1997)).
Of the 127,000 patients in the US currently with active B-NHL, approximately 50% of these patients present with the DLBCL (intermediate grade) sub-type (Morton et al., Blood 107, 265-276 (2002)). Despite Rituxan plus cyclophosphamide, adriamycin, vincristine, prednisone (CHOP) standard of care therapy for DLBCL patients, almost 50% relapse. Therefore an unmet medical need remains in this disease as well.